{
  "event": {
    "ticker": "CORT",
    "company": "Corcept Therapeutics Incorporated",
    "drug": "relacorilant",
    "application_type": "NDA",
    "indication": "Cushing's syndrome (endogenous hypercortisolism); resubmission after a complete response letter. The first-cycle application sought hypertension secondary to hypercortisolism",
    "pdufa_date": "2026-12-17"
  },
  "display": {
    "company": "Corcept",
    "drug": "relacorilant",
    "indication_en": "Cushing's syndrome",
    "indication_zh": "库欣综合征"
  },
  "probability_approval": 0.4,
  "confidence": "low",
  "base_rate_used": 0.76,
  "key_factors": [
    {
      "factor": "FDA's rejection letter found the efficacy evidence insufficient",
      "direction": "-",
      "step": "large",
      "evidence": "FDA's complete response letter (effective 30 December 2025; corrected version signed 28 January 2026) says the evidence \"is not sufficient to demonstrate the effectiveness of relacorilant for the proposed indication\". GRACE \"met its primary endpoint\", but \"the analysis was conducted in a highly enriched population\": of 102 patients with hypertension at baseline, 40 (39%) left during the open-label phase and only 46 (45%) entered the randomized-withdrawal phase, so the result \"likely overestimates the treatment effect\" in the intended population. GRADIENT, the parallel-group placebo-controlled trial, \"did not meet its primary efficacy endpoint\": 24-hour systolic pressure fell 5.8 mm Hg on relacorilant and 5 mm Hg on placebo (difference -0.85 mm Hg; 95% CI -6.7 to 4.9; p=0.77). Corcept's post hoc analysis in 33 patients with Cushing's syndrome (difference -10.4 mm Hg; nominal p=0.03) included only 8 of 16 and 13 of 17 patients; FDA's own analysis with a different method for missing data gave -4.9 mm Hg (95% CI -15.3 to 5.6; nominal p=0.36). The published GRACE paper shows how small the pivotal comparison was: 21 patients on relacorilant and 22 on placebo (odds ratio 0.17; 95% CI 0.04-0.77; p=0.022). FDA added that before submission it had told Corcept \"on several occasions\" of its concerns and \"to expect significant review issues\".",
      "source": "FDA Corrected Complete Response Letter, NDA 219398, signed 2026-01-28: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf; Pivonello et al., Lancet Diabetes Endocrinol 2026;14(4):291-304: https://pubmed.ncbi.nlm.nih.gov/41730814/"
    },
    {
      "factor": "The resubmission adds analyses, not the new clinical data FDA asked for",
      "direction": "-",
      "step": "large",
      "evidence": "Under \"Path forward\" the letter says: \"you will need to provide new clinical data to demonstrate that relacorilant treatment results in a clinically meaningful\" effect (the endpoint is redacted), and offers a meeting \"to discuss a feasible controlled clinical trial design using a novel endpoint such as a composite of signs and symptoms\". FDA also reviewed the exploratory findings on body weight and blood glucose and was \"not persuaded that such benefits were observed\". The resubmission of 17 June 2026, in Corcept's words, \"includes additional analyses of data included in the original NDA submission\" and rests on the same studies: GRACE, GRADIENT, the long-term extension study and earlier trials. ClinicalTrials.gov lists no new controlled trial of relacorilant in Cushing's syndrome. What the analyses are, and what they show, is not public. Efficacy problems are historically the hardest to cure: in FDA's own study of new molecular entities first submitted in 2000-2012, efficacy deficiencies were present in 61 of the 80 applications never approved, against 28 of the 71 approved after resubmission. The 76% base rate describes first-time applications.",
      "source": "FDA Corrected Complete Response Letter, NDA 219398: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf; Corcept 8-K exhibit 99.1, 2026-06-17: https://www.sec.gov/Archives/edgar/data/1088856/000119312526274258/d159941dex991.htm; ClinicalTrials.gov, studies of relacorilant: https://clinicaltrials.gov/search?intr=relacorilant; Sacks et al., JAMA 2014;311(4):378-84: https://pubmed.ncbi.nlm.nih.gov/24449316/"
    },
    {
      "factor": "After the rejection, FDA itself asked for further analyses and started a new review",
      "direction": "+",
      "step": "large",
      "evidence": "Corcept met FDA in April 2026. Its quarterly report says: \"In April 2026, the FDA asked us to conduct additional analyses of the data included in our NDA. Based on the outcome of those analyses, we resubmitted our NDA to the FDA on June 17, 2026. The FDA has assigned a Prescription Drug User Fee Act target date of December 17, 2026 to complete its review.\" On 27 May the chief executive said the agency \"has told us to expect\" a goal date six months after submission, and on 29 July that \"the FDA accepted our resubmission\". Six months is FDA's goal for a Class 2 resubmission; Corcept has not used the term. In February Corcept had named three possible outcomes of the meeting: resubmission with additional analyses, a formal appeal, or a new study. The lightest of the three followed. FDA's letter had warned that \"a partial response to this letter will not be processed as a resubmission\", yet FDA started a review clock on a package without the new clinical data the letter called for. Limits: every account of the April request comes from Corcept, FDA has not commented on it in public, and accepting a resubmission for review is not a finding that it is adequate.",
      "source": "Corcept 10-Q filed 2026-07-29: https://www.sec.gov/Archives/edgar/data/1088856/000162828026050613/cort-20260630.htm; Corcept press release, 2026-05-27: https://www.biospace.com/press-releases/corcept-to-resubmit-its-new-drug-application-for-relacorilant-as-a-treatment-for-patients-with-cushings-syndrome; Q1 2026 results call transcript, 2026-04-30: https://www.fool.com/earnings/call-transcripts/2026/05/04/corcept-cort-q1-2026-earnings-transcript/; Q2 2026 results call transcript, 2026-07-29: https://www.investing.com/news/transcripts/earnings-call-transcript-corcept-therapeutics-q2-2026-revenue-beat-lifts-stock-93CH-4821896; Q4 2025 results call transcript, 2026-02-24: https://www.fool.com/earnings/call-transcripts/2026/05/04/corcept-cort-q4-2025-earnings-transcript/; PDUFA performance goals FY2023-2027, section I.A.1: https://www.fda.gov/media/151712/download; FDA Corrected Complete Response Letter: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf"
    },
    {
      "factor": "A liver-injury signal with daily dosing",
      "direction": "-",
      "step": "medium",
      "evidence": "After its safety review FDA \"concluded that relacorilant is associated with drug induced liver injury (DILI)\". Among 303 people who received the drug, four cases were assessed as probable DILI; one patient's ALT reached 1952 U/L, \"more than 50 times the upper limit of normal\". None met Hy's law criteria. FDA wrote that more cases may occur with longer exposure after approval and that \"we cannot conclude that relacorilant has a favorable benefit risk assessment for the proposed indication\". It also recommended a proposal for \"DILI risk mitigation strategies including appropriate labeling warnings, routine monitoring requirements, enhanced pharmacovigilance, and post-market evaluation\", which suggests the risk could be handled in labeling once benefit is shown. Corcept disputes the finding: on 24 February 2026 its chief development officer said the company's assessment, confirmed by an external independent safety committee, was that the endocrinology programme had no cases of drug-induced liver injury. The label of Lifyorli, approved in March 2026 at 150 mg on three days around each chemotherapy infusion, has no liver-injury warning; treatment of Cushing's syndrome is daily and long-term (100 to 400 mg a day in GRACE).",
      "source": "FDA Corrected Complete Response Letter, NDA 219398: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf; Q4 2025 results call transcript, 2026-02-24: https://www.fool.com/earnings/call-transcripts/2026/05/04/corcept-cort-q4-2025-earnings-transcript/; Lifyorli prescribing information: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fcebfb5-19d6-4f63-b852-999d68a13729; Pivonello et al. 2026: https://pubmed.ncbi.nlm.nih.gov/41730814/"
    },
    {
      "factor": "The pivotal trial met its planned endpoint and the mechanism is established",
      "direction": "+",
      "step": "small",
      "evidence": "FDA's letter accepts that GRACE \"met its primary endpoint\": among patients whose blood pressure had responded, those switched to placebo lost control more often than those kept on relacorilant (proportion difference 34%; odds ratio 0.17; p=0.022). In GRADIENT (137 patients, double-blind, 22 weeks) the secondary endpoints favoured relacorilant with nominal significance, as reported by Corcept: body weight -3.9 kg against placebo (p=0.0001), fasting glucose -22.2 mg/dL (p=0.002) and HbA1c -0.3 percentage points (p=0.019). The letter itself says \"relacorilant may have benefit for the broader indication\", and since the resubmission Corcept describes the application as for \"patients with Cushing's syndrome\" where in December 2025 it said \"hypertension secondary to hypercortisolism\"; the indication actually proposed is not public. Relacorilant blocks the same receptor as mifepristone (Korlym), marketed for Cushing's syndrome since 2012, and has orphan designation. Against this, FDA was \"not persuaded\" by the weight and glucose findings, a failed trial's secondary endpoints carry little formal weight, and other approved medicines exist.",
      "source": "FDA Corrected Complete Response Letter: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf; Pivonello et al. 2026: https://pubmed.ncbi.nlm.nih.gov/41730814/; Corcept 8-K exhibit 99.1, 2024-10-30: https://www.sec.gov/Archives/edgar/data/1088856/000162828024044318/exhibit991pressrelease10-3.htm; Corcept 8-K exhibit 99.1, 2025-12-31: https://www.sec.gov/Archives/edgar/data/1088856/000119312525338184/d50993dex991.htm; Corcept 8-K exhibit 99.1, 2026-06-17: https://www.sec.gov/Archives/edgar/data/1088856/000119312526274258/d159941dex991.htm"
    },
    {
      "factor": "FDA has reopened several rejected applications since its leadership changed",
      "direction": "+",
      "step": "small",
      "evidence": "Commissioner Marty Makary's resignation was announced on 12 May 2026, and the acting head of FDA's drug centre (CDER), Tracy Beth Høeg, was dismissed days later. Michael Davis, the deputy director, who had earlier worked in the Office of New Drugs, became acting CDER director and was named permanent director on 8 September. BioPharma Dive reported that the acting leadership \"largely reverted toward more traditional and flexible decision-making, reversing some positions on previously rejected or delayed drugs\"; BioCentury counted at least seven therapies approved, revived or reopened since March 2026. Limits: the reversals named in press reports (Replimune's RP1, uniQure's Huntington's gene therapy, Atara's Ebvallo, Regenxbio's Hunter syndrome gene therapy) were at the biologics centre, not CDER; in June 2026 CDER still tied Disc Medicine's response to its rejection of bitopertin to results from an ongoing Phase 3 trial; and FDA's request to Corcept came in April, before these changes. No public record connects the two.",
      "source": "STAT, 2026-05-12: https://www.statnews.com/2026/05/12/fda-commissioner-marty-makary-resigns-kyle-diamantas-acting/; pharmaphorum, 2026-05-18: https://pharmaphorum.com/news/after-refusing-resign-cder-head-hoeg-fired; BioPharma Dive, 2026-09-08: https://www.biopharmadive.com/news/fda-mikhail-davis-cber-cder-director-hhs/829886/; BioCentury, 2026-06-02: https://www.biocentury.com/article/659645/fda-reviving-drugs-derailed-under-makary-and-prasad; BioSpace, 2026-05-07: https://www.biospace.com/fda/fda-reverses-course-on-atara-pierre-fabres-twice-rejected-cell-therapy-after-prasads-exit; BioSpace, 2026-08-05: https://www.biospace.com/fda/chaotic-adcomms-threaten-to-derail-fdas-bid-to-renew-trust-after-makary-prasad; Disc Medicine release, 2026-06-09: https://www.globenewswire.com/news-release/2026/06/09/3308825/0/en/Disc-Medicine-Provides-Update-from-FDA-Type-A-Meeting-for-Bitopertin-in-Erythropoietic-Protoporphyria.html"
    },
    {
      "factor": "Product quality is not in question: the same capsules were approved in March 2026",
      "direction": "+",
      "step": "small",
      "evidence": "FDA approved relacorilant 25 mg and 100 mg capsules as Lifyorli for ovarian cancer on 25 March 2026 (NDA 220641), three and a half months before its goal date of 11 July 2026. The Cushing's syndrome letter lists deficiencies only under \"Clinical and Statistical\"; it has no product-quality or facility section. Manufacturing problems are a frequent reason for FDA rejections, and that cause is largely absent here. The ovarian cancer approval does not bear on efficacy in Cushing's syndrome: it rested on a different trial in a different disease.",
      "source": "FDA Drugs@FDA record for NDA 220641: https://api.fda.gov/drug/drugsfda.json?search=application_number:%22NDA220641%22; Lifyorli prescribing information: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fcebfb5-19d6-4f63-b852-999d68a13729; Corcept 8-K exhibit 99.1, 2026-03-25: https://www.sec.gov/Archives/edgar/data/1088856/000119312526123543/d123475dex991.htm; FDA Corrected Complete Response Letter, NDA 219398: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf"
    },
    {
      "factor": "The company's confident account has diverged from FDA's before",
      "direction": "-",
      "step": "small",
      "evidence": "Corcept says the analyses FDA requested had a \"positive outcome\", cites \"the productive tenor of our discussions\" and expects a decision by 17 December 2026. Its record in describing FDA's views is mixed. On 31 December 2025 it said FDA had acknowledged that GRADIENT \"provided confirmatory evidence\", and its quarterly report of 29 July 2026 still says so; the letter FDA published says GRADIENT \"did not meet its primary efficacy endpoint\". On 24 February 2026 its chief business officer said FDA had not told the company it \"would face significant review issues\"; the letter says FDA told it \"to expect significant review issues\". FDA reissued the letter on 28 January 2026 in response to a communication from Corcept, noting that the original \"contained no errors\". Since the resubmission there is no public record of labeling discussions, of an advisory committee meeting, or of any FDA comment on the new analyses. On 23 September 2026 Corcept announced that the president of its endocrinology division would retire on 1 October, 11 weeks before the goal date, and stay on as an adviser; his successor built the Lifyorli sales organisation. The announcement does not mention relacorilant.",
      "source": "Corcept press release, 2026-05-27: https://www.biospace.com/press-releases/corcept-to-resubmit-its-new-drug-application-for-relacorilant-as-a-treatment-for-patients-with-cushings-syndrome; Corcept 8-K exhibit 99.1, 2026-07-29: https://www.sec.gov/Archives/edgar/data/1088856/000162828026050607/cort072926ex991pressrelease.htm; Corcept 8-K exhibit 99.1, 2025-12-31: https://www.sec.gov/Archives/edgar/data/1088856/000119312525338184/d50993dex991.htm; Corcept 10-Q filed 2026-07-29: https://www.sec.gov/Archives/edgar/data/1088856/000162828026050613/cort-20260630.htm; Q4 2025 results call transcript, 2026-02-24: https://www.fool.com/earnings/call-transcripts/2026/05/04/corcept-cort-q4-2025-earnings-transcript/; FDA Corrected Complete Response Letter: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf; BioSpace, 2026-02-02: https://www.biospace.com/fda/fda-warned-corcept-of-significant-review-issues-for-rejected-drug-in-early-meetings; FDA advisory committee page, 2026 meeting materials: https://www.fda.gov/advisory-committees/endocrinologic-and-metabolic-drugs-advisory-committee/2026-meeting-materials-endocrinologic-and-metabolic-drugs-advisory-committee; Corcept 8-K and exhibit 99.1, 2026-09-23: https://www.sec.gov/Archives/edgar/data/1088856/000119312526398561/d148256d8k.htm; https://www.sec.gov/Archives/edgar/data/1088856/000119312526398561/d148256dex991.htm"
    }
  ],
  "manufacturing_risk": {
    "level": "low",
    "why": "Relacorilant 25 mg and 100 mg soft gelatin capsules were approved as Lifyorli on 25 March 2026 (NDA 220641), so the drug substance and the capsule manufacture passed FDA review this year. FDA's complete response letter for the Cushing's syndrome application lists deficiencies only under \"Clinical and Statistical\" and has no product-quality or facility section. Corcept has supplied Korlym commercially since 2012. What cannot be judged: Corcept does not name its contract manufacturers in its SEC filings, so their inspection records cannot be checked; daily dosing for Cushing's syndrome (100 to 400 mg in GRACE) needs different packaging from the co-packaged oncology dose cards; and there is no public record of any inspection tied to this resubmission."
  },
  "what_would_change_my_mind": [
    "Up: Corcept discloses labeling discussions with FDA, or FDA requests about liver-monitoring language or post-marketing studies.",
    "Up: it becomes public what the requested analyses were and that FDA defined them in advance as a basis for approval; or CDER approves another drug it had rejected on efficacy grounds after re-analysis of existing trials.",
    "Down: Corcept registers or announces a new controlled trial of relacorilant in Cushing's syndrome, or says FDA has asked for additional clinical data.",
    "Down: Corcept's next quarterly report, expected in early November 2026, adds cautionary wording about the review or leaves relacorilant out of its near-term growth statements.",
    "Down: new cases of serious liver injury are reported in the long-term extension study or with Lifyorli, or a liver warning is added to the Lifyorli label.",
    "Void rather than no: Corcept withdraws the application before FDA acts."
  ],
  "summary_en": "FDA approval of relacorilant for Cushing's syndrome in this review cycle is put at 40%, below the 76% base rate for first-time applications from smaller companies. FDA rejected the drug in December 2025: it judged the efficacy evidence insufficient (the placebo-controlled GRADIENT trial missed its primary endpoint, p=0.77), found four probable cases of drug-induced liver injury, and asked for new clinical data. The resubmission contains only further analyses of the same trials. Approval remains a real possibility because FDA itself requested those analyses in April 2026 and accepted the resubmission for a six-month review. The same capsules were approved for ovarian cancer in March 2026, so manufacturing is not the obstacle. What the new analyses show is not public.",
  "summary_zh": "FDA 在本轮审评中批准 relacorilant 用于库欣综合征的概率估计为 40%，低于小公司首次申请 76% 的基准。FDA 在 2025 年 12 月拒绝了该药：认为疗效证据不足（安慰剂对照的 GRADIENT 试验未达主要终点，p=0.77），认定有 4 例很可能的药物性肝损伤，并要求提供新的临床数据。这次重新提交只补充了对同一批试验的分析。之所以仍有相当机会，是因为这些分析是 FDA 在 2026 年 4 月主动要求的，重新提交已被受理并进入六个月审评；同样的胶囊今年 3 月已获批用于卵巢癌，生产不是障碍。新分析的结果尚未公开。",
  "sources": [
    "FDA Corrected Complete Response Letter, NDA 219398 (relacorilant capsules), signed 2026-01-28, action date 2025-12-30: https://download.open.fda.gov/crl/CRL_NDA219398_20260128.pdf",
    "Corcept 10-Q for Q2 2026, filed 2026-07-29: https://www.sec.gov/Archives/edgar/data/1088856/000162828026050613/cort-20260630.htm",
    "Corcept 8-K exhibit 99.1, 2026-07-29 (second-quarter results): https://www.sec.gov/Archives/edgar/data/1088856/000162828026050607/cort072926ex991pressrelease.htm",
    "Corcept 8-K exhibit 99.1, 2026-06-17 (resubmission): https://www.sec.gov/Archives/edgar/data/1088856/000119312526274258/d159941dex991.htm",
    "Corcept press release, 2026-05-27 (plan to resubmit): https://www.biospace.com/press-releases/corcept-to-resubmit-its-new-drug-application-for-relacorilant-as-a-treatment-for-patients-with-cushings-syndrome",
    "Corcept 8-K exhibit 99.1, 2025-12-31 (complete response letter): https://www.sec.gov/Archives/edgar/data/1088856/000119312525338184/d50993dex991.htm",
    "Corcept 8-K exhibit 99.1, 2024-10-30 (GRADIENT results): https://www.sec.gov/Archives/edgar/data/1088856/000162828024044318/exhibit991pressrelease10-3.htm",
    "Corcept 8-K exhibit 99.1, 2026-03-25 (Lifyorli approval): https://www.sec.gov/Archives/edgar/data/1088856/000119312526123543/d123475dex991.htm",
    "Corcept 8-K, 2026-09-23 (leadership transition): https://www.sec.gov/Archives/edgar/data/1088856/000119312526398561/d148256d8k.htm",
    "Corcept 8-K exhibit 99.1, 2026-09-23: https://www.sec.gov/Archives/edgar/data/1088856/000119312526398561/d148256dex991.htm",
    "Corcept Q4 2025 results call transcript, 2026-02-24: https://www.fool.com/earnings/call-transcripts/2026/05/04/corcept-cort-q4-2025-earnings-transcript/",
    "Corcept Q1 2026 results call transcript, 2026-04-30: https://www.fool.com/earnings/call-transcripts/2026/05/04/corcept-cort-q1-2026-earnings-transcript/",
    "Corcept Q2 2026 results call transcript, 2026-07-29: https://www.investing.com/news/transcripts/earnings-call-transcript-corcept-therapeutics-q2-2026-revenue-beat-lifts-stock-93CH-4821896",
    "Pivonello R, et al. GRACE trial. Lancet Diabetes Endocrinol 2026;14(4):291-304: https://pubmed.ncbi.nlm.nih.gov/41730814/",
    "Sacks LV, et al. Reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA 2014;311(4):378-84: https://pubmed.ncbi.nlm.nih.gov/24449316/",
    "FDA Drugs@FDA record for NDA 220641 (Lifyorli), via openFDA: https://api.fda.gov/drug/drugsfda.json?search=application_number:%22NDA220641%22",
    "Lifyorli prescribing information (DailyMed): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6fcebfb5-19d6-4f63-b852-999d68a13729",
    "ClinicalTrials.gov, studies of relacorilant (GRACE NCT03697109, GRADIENT NCT04308590, extension NCT03604198): https://clinicaltrials.gov/search?intr=relacorilant",
    "PDUFA Reauthorization Performance Goals and Procedures FY2023-2027: https://www.fda.gov/media/151712/download",
    "FDA, Endocrinologic and Metabolic Drugs Advisory Committee, 2026 meeting materials: https://www.fda.gov/advisory-committees/endocrinologic-and-metabolic-drugs-advisory-committee/2026-meeting-materials-endocrinologic-and-metabolic-drugs-advisory-committee",
    "BioSpace, 2026-02-02: https://www.biospace.com/fda/fda-warned-corcept-of-significant-review-issues-for-rejected-drug-in-early-meetings",
    "STAT, 2026-05-12: https://www.statnews.com/2026/05/12/fda-commissioner-marty-makary-resigns-kyle-diamantas-acting/",
    "pharmaphorum, 2026-05-18: https://pharmaphorum.com/news/after-refusing-resign-cder-head-hoeg-fired",
    "BioPharma Dive, 2026-09-08: https://www.biopharmadive.com/news/fda-mikhail-davis-cber-cder-director-hhs/829886/",
    "BioCentury, 2026-06-02: https://www.biocentury.com/article/659645/fda-reviving-drugs-derailed-under-makary-and-prasad",
    "BioSpace, 2026-05-07: https://www.biospace.com/fda/fda-reverses-course-on-atara-pierre-fabres-twice-rejected-cell-therapy-after-prasads-exit",
    "BioSpace, 2026-08-05: https://www.biospace.com/fda/chaotic-adcomms-threaten-to-derail-fdas-bid-to-renew-trust-after-makary-prasad",
    "Disc Medicine release, 2026-06-09: https://www.globenewswire.com/news-release/2026/06/09/3308825/0/en/Disc-Medicine-Provides-Update-from-FDA-Type-A-Meeting-for-Bitopertin-in-Erythropoietic-Protoporphyria.html"
  ],
  "zh": {
    "indication": "库欣综合征（内源性皮质醇增多症）；收到完全回应函（CRL）后重新提交。首轮申请的拟定适应症为皮质醇增多症继发的高血压",
    "key_factors": [
      {
        "factor": "FDA 的完全回应函（CRL）认定疗效证据不足",
        "evidence": "FDA 的完全回应函（CRL）（生效日期 2025 年 12 月 30 日；更正版签发于 2026 年 1 月 28 日）写明，现有证据不足以证明 relacorilant 对拟定适应症有效。GRACE 达到了主要终点，但函中指出分析是在高度富集的人群中做的：基线有高血压的 102 名患者中，40 名（39%）在开放标签阶段退出，只有 46 名（45%）进入随机撤药阶段，因此结果很可能高估了药物在目标人群中的疗效。平行分组、安慰剂对照的 GRADIENT 未达主要疗效终点：24 小时收缩压在 relacorilant 组下降 5.8 mm Hg，安慰剂组下降 5 mm Hg（组间差 -0.85 mm Hg；95% CI -6.7 至 4.9；p=0.77）。Corcept 在 33 名库欣综合征患者中做的事后分析（组间差 -10.4 mm Hg；名义 p=0.03）只纳入了 16 名中的 8 名和 17 名中的 13 名；FDA 换用另一种缺失数据处理方法自行分析，结果为 -4.9 mm Hg（95% CI -15.3 至 5.6；名义 p=0.36）。已发表的 GRACE 论文显示，关键比较的规模很小：relacorilant 组 21 人，安慰剂组 22 人（比值比 0.17；95% CI 0.04-0.77；p=0.022）。FDA 还写道，申报前已多次向 Corcept 说明顾虑，并提醒它若提交申请，要有遇到重大审评问题的准备。"
      },
      {
        "factor": "重新提交只补充了分析，没有 FDA 要求的新临床数据",
        "evidence": "完全回应函（CRL）在“后续路径”一节写明：公司需要提供新的临床数据，证明 relacorilant 治疗能带来有临床意义的效果（具体终点被涂黑）；FDA 还表示愿意开会讨论可行的对照临床试验设计，采用新型终点，例如体征和症状的复合终点。对于体重和血糖方面的探索性结果，FDA 审阅后表示，并未被说服这些获益确实存在。按 Corcept 的说法，2026 年 6 月 17 日的重新提交包含对最初 NDA 中数据的补充分析，依据仍是同一批研究：GRACE、GRADIENT、长期扩展研究和更早期的试验。ClinicalTrials.gov 上没有登记新的 relacorilant 治疗库欣综合征的对照试验。这些分析的具体内容和结果均未公开。从历史上看，疗效问题最难补救：FDA 自己对 2000-2012 年首次申报的新分子实体所做的研究显示，始终未获批的 80 项申请中有 61 项存在疗效缺陷，而重新提交后获批的 71 项中只有 28 项。76% 的基准描述的是首次申请。"
      },
      {
        "factor": "被拒之后，FDA 主动要求补充分析，并启动了新一轮审评",
        "evidence": "Corcept 于 2026 年 4 月与 FDA 开会。其季度报告写道：2026 年 4 月，FDA 要求公司对 NDA 中的数据做补充分析；公司根据分析结果，于 2026 年 6 月 17 日重新提交了 NDA；FDA 已把完成审评的 PDUFA 目标日期定为 2026 年 12 月 17 日。首席执行官在 5 月 27 日表示，FDA 已告知公司，目标日期将定在提交后六个月；7 月 29 日又表示，FDA 已受理这次重新提交。六个月是 FDA 对 2 类重新提交（Class 2）的审评时限；Corcept 自己没有用过这个说法。公司在 2 月曾列出这次会议可能的三种结果：附带补充分析重新提交、正式申诉，或者开展新研究。最后走的是三者中最轻的一条。完全回应函（CRL）曾提醒，不完整的答复不会被当作重新提交处理；而 FDA 仍对一份不含新临床数据的材料启动了审评计时。局限在于：关于 4 月这项要求的说法全部出自 Corcept，FDA 没有就此公开表态；受理重新提交也不等于认定材料已经足够。"
      },
      {
        "factor": "每日给药下出现肝损伤信号",
        "evidence": "FDA 在安全性审评后认定，relacorilant 与药物性肝损伤（DILI）相关。在 303 名用过该药的受试者中，有 4 例被评估为很可能的 DILI；其中一名患者的 ALT 升至 1952 U/L，超过正常上限的 50 倍。没有病例符合 Hy's law 标准。FDA 写道，获批后随着用药时间延长，可能出现更多病例，目前无法认定 relacorilant 在拟定适应症上的获益风险评估为正面。FDA 同时建议公司提交 DILI 风险控制方案，包括适当的标签警示、常规监测要求、强化药物警戒和上市后评估；这意味着只要获益得到证明，这一风险可以通过标签来管理。Corcept 不认同这一结论：其首席开发官在 2026 年 2 月 24 日表示，公司的评估是内分泌项目中没有药物性肝损伤病例，外部独立安全委员会也确认了这一点。Lifyorli 于 2026 年 3 月获批，用法是每次化疗输注前后共三天、每天 150 mg，其标签没有肝损伤警示；而库欣综合征需要每日长期服药（GRACE 中为每日 100 至 400 mg）。"
      },
      {
        "factor": "关键试验达到了预设终点，作用机制也早有先例",
        "evidence": "FDA 的函件承认 GRACE 达到了主要终点：在血压已有应答的患者中，改用安慰剂的人比继续服用 relacorilant 的人更容易失去血压控制（比例差 34%；比值比 0.17；p=0.022）。在 GRADIENT（137 名患者，双盲，22 周）中，按 Corcept 的报告，次要终点以名义显著性偏向 relacorilant：体重相对安慰剂 -3.9 kg（p=0.0001），空腹血糖 -22.2 mg/dL（p=0.002），HbA1c -0.3 个百分点（p=0.019）。函件本身也写到，relacorilant 可能对更宽的适应症有益；重新提交以来，Corcept 把这项申请表述为用于库欣综合征患者，而 2025 年 12 月的说法是皮质醇增多症继发的高血压，实际申报的适应症并未公开。Relacorilant 阻断的受体与 mifepristone（Korlym）相同，后者自 2012 年起用于库欣综合征；该药还拥有孤儿药资格。另一方面，FDA 表示体重和血糖方面的结果没有说服它，失败试验的次要终点在形式上分量很轻，市场上也已有其他获批药物。"
      },
      {
        "factor": "FDA 领导层更替后，已有多项被拒申请重获机会",
        "evidence": "FDA 局长 Marty Makary 辞职的消息于 2026 年 5 月 12 日公布，药品审评与研究中心（CDER）代理主任 Tracy Beth Høeg 几天后被免职。副主任 Michael Davis 此前曾在新药办公室任职，随后出任 CDER 代理主任，并于 9 月 8 日被正式任命为主任。BioPharma Dive 报道称，代理领导层基本回到了更传统、也更灵活的决策方式，并改变了此前对一些被拒或被搁置药物的立场；BioCentury 统计，自 2026 年 3 月以来至少有 7 种疗法获批、被重启或重新打开了通道。局限在于：媒体点名的转向案例（Replimune 的 RP1、uniQure 的亨廷顿病基因疗法、Atara 的 Ebvallo、Regenxbio 的亨特综合征基因疗法）都出在生物制品中心，而不是 CDER；2026 年 6 月，CDER 仍要求 Disc Medicine 用一项正在进行的 3 期试验的结果来答复 bitopertin 被拒一事；而 FDA 向 Corcept 提出要求是在 4 月，早于上述人事变动。公开资料未见两者之间有关联。"
      },
      {
        "factor": "产品质量不成问题：同样的胶囊已于 2026 年 3 月获批",
        "evidence": "FDA 于 2026 年 3 月 25 日批准 relacorilant 25 mg 和 100 mg 胶囊以 Lifyorli 之名用于卵巢癌（NDA 220641），比 2026 年 7 月 11 日的目标日期早了三个半月。针对库欣综合征申请的函件只在“临床与统计”项下列出缺陷，没有产品质量或生产设施方面的章节。生产问题是 FDA 拒批的常见原因，而这一因素在这里基本不存在。卵巢癌的获批并不能说明该药在库欣综合征中的疗效：那次批准依据的是另一种疾病中的另一项试验。"
      },
      {
        "factor": "公司的乐观说法此前曾与 FDA 的说法不一致",
        "evidence": "Corcept 称 FDA 要求的分析结果积极，并提到与 FDA 的沟通富有成效，预计 2026 年 12 月 17 日前会有决定。但它转述 FDA 意见的记录好坏参半。2025 年 12 月 31 日，公司称 FDA 承认 GRADIENT 提供了佐证性证据，2026 年 7 月 29 日的季度报告仍这样写；而 FDA 公布的函件写的是 GRADIENT 未达主要疗效终点。2026 年 2 月 24 日，公司首席商务官表示，FDA 没有告诉过公司会遇到重大审评问题；函件则写明，FDA 曾提醒公司要预期重大审评问题。FDA 于 2026 年 1 月 28 日针对 Corcept 的一份来函重新签发了该函，并注明原函没有错误。重新提交以来，公开资料未见标签讨论，未见咨询委员会会议安排，也未见 FDA 对新分析的任何表态。2026 年 9 月 23 日，Corcept 宣布内分泌业务总裁将于 10 月 1 日退休，距目标日期还有 11 周，此后留任顾问；继任者曾组建 Lifyorli 的销售团队。公告中没有提到 relacorilant。"
      }
    ],
    "manufacturing_risk_why": "Relacorilant 25 mg 和 100 mg 软胶囊已于 2026 年 3 月 25 日以 Lifyorli 之名获批（NDA 220641），原料药和胶囊的生产今年已通过 FDA 审评。FDA 针对库欣综合征申请的完全回应函（CRL）只在“临床与统计”项下列出缺陷，没有产品质量或生产设施方面的章节。Corcept 自 2012 年起就在商业化供应 Korlym。无法判断的部分：Corcept 在 SEC 文件中没有披露合同生产商的名称，其检查记录无从查核；库欣综合征需每日给药（GRACE 中为 100 至 400 mg），包装形式不同于肿瘤适应症的组合包装剂量卡；公开资料也未见与这次重新提交相关的任何检查。",
    "what_would_change_my_mind": [
      "上调：Corcept 披露已与 FDA 进行标签讨论，或 FDA 就肝功能监测措辞、上市后研究提出要求。",
      "上调：FDA 所要求分析的具体内容公开，且显示 FDA 事先已把它们定为批准的依据；或 CDER 在仅对已有试验重新分析的情况下，批准了另一款曾因疗效问题被拒的药物。",
      "下调：Corcept 登记或宣布开展新的 relacorilant 治疗库欣综合征的对照试验，或表示 FDA 要求补充临床数据。",
      "下调：Corcept 预计于 2026 年 11 月初发布的下一份季度报告对审评增加了谨慎措辞，或不再把 relacorilant 列入近期增长的表述。",
      "下调：长期扩展研究或 Lifyorli 上市后出现新的严重肝损伤病例，或 Lifyorli 标签增加肝脏方面的警示。",
      "作废而非判否：Corcept 在 FDA 作出决定前撤回申请。"
    ]
  },
  "recorded_at": "2026-10-05T08:21:32+00:00"
}